CA1086305A

CA1086305A - Depot-steroid esters

Info

Publication number: CA1086305A
Application number: CA268,172A
Authority: CA
Inventors: Rudolf Wiechert; Dieter Bittler; Paul-Eberhard Schulze; Bernard Acksteiner; Ulrich Speck
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1975-12-19
Filing date: 1976-12-17
Publication date: 1980-09-23
Also published as: PH13907A; NO147717B; DK146629B; FR2335231A1; SE428930B; DE2558076A1; DE2558076C2; NO803670L; AU507111B2; DK566076A; FI763544A; IE44320B1; GB1554199A; MX3798E; NO145620B; JPS6131115B2; SE7614107L; BG31504A3; PL105525B1; YU293176A

Abstract

ABSTRACT OF THE DISCLOSURE
Steroid esters having depot action in which the 17-position is substituted by i) an alkynyl radical in the .alpha.-position or an acetyl radical in the R-position, and by ii) a group of the general formula -O-CO-Z in which Z represents X-OH, Y-CO-OH, X-O-CO-Y-CO-OH, X-O-CO-R, Y-CO-OR, X-O-CO-Y-CO-OR, or X-O-SO2-R, in which X represents a saturated hydrocarbon radical having from 1 to 6 carbon atoms which may be uninterrupted or interrupted by one or more of the same or different atoms selected from oxygen and sulphur, and may be unsubstituted or substituted by one or more of the same or different substituents selected from -OH, -OCOR
and -OSO2R groups, Y represents a direct bond, an aliphatic radical which may be uninterrupted or interrupted by one or more of the same or different atoms selected from oxygen and sulphur, and which has from 1 to 3 carbon atoms in the case where Y is bound through -O-CO- to the steroid residue, or from 1 to 16 carbon atoms in the case where Y is bound through -O-CO- to X, or a cyclohexylene, cyclopentylene or phenylene group which may be unsubstituted or substituted by one or more of the same or different substituents selected from methyl and ethyl groups, and, R represents a hydrocarbon radical having from 1 to 22 carbon atoms

Description

~0t36305 This invention relates to steroid esters having a depot action.
We have now found that a steroid in which the 17-position is substi:tuted by i) an alkynyl radical in the ~-position or an acetyl :
radical in the ~-position, and by ii) a group of the general formula -O-CO-Z in which Z represents X-OH, Y-CO-OH, X-O-CO-Y-CO-OH, X-O-CO-R, Y-CO-OR, X-O-CO-Y-CO-OR or X-O-SO2-R, in which X represents a sa*urated hydrocarbon radical having ~ :
from 1 to 6 carbon atoms which may be uninterrupted or interrupted by one or more of the same or different atoms selected from oxygen and sulphur, and may be unsubstituted or substituted by -one or more of the same or different substitutents selected from -OH, -OCOR and -OSO2R groups, Y represents a direct bond, an aliphatic radical which may be uninterrupted or interrupted by one or more of the same or different atoms selected from oxygen and sulphur, and which has from 1 to 3 carbon atoms in the case where Y is bound -through -Q-CO- to the steroid residue, or from 1 to 16 carbon atoms in the case where Y is bound through -O-CO- to X, or a cyclohexylene, cyclopentylene or phenylene group which may be unsu~stituted or substituted by one or more of the same or different substituents selected from methyl and ethyl groups, and R represents a hydrocarbon radical having from 1 to 22 carbon atoms, and its physiologically tolerable salts have a depot effect.
Accordingly, the present invention provides such a compound and a salt, especially a physiolgically tolerable salt, of such a compound.

The remainder of the steroid molecule may be unsubstit-uted or substituted, saturated or unsaturated, provided biological ~086305 activity is maintained.
The steroid may contain a 10-methyl group, or such a group may be absent; it may contain a 13-methyl, -ethyl, -propyl or -isopropyl group.
An alkynyl radical in the 17~-position may, for example be a chlorine-substituted alkynyl group, e.g. chloroethynyl; an acetyl radical in the 17~-position may be, for example, a fluorine-substituted acetyl group as in FH2C-CO~
A hydrocarbon radical represented by R may be unsub-stituted or substituted, the total number of carbon atoms beingup to 22 and may optionally be interrupted by one or more of the same or different atoms selected from oxygen and sulphur.
The saturated radical represented by X contains non-cyclic and/or cyclic groups, and is usually straight or branched alkylene.
The aliphatic radical represented by Y may be unsatur-ated or saturated, but is usually saturated.
Thus, this invention especially provides an ester of the general formula O

~ -II-Z

A ¦ B I (I) ,,~ /' in which the rings A, B, C and D may be unsubstituted or sub-stituted and may be saturated or unsaturated, Rlo represents a hydrogen atom or a methyl group, R13 represents an alkyl group having from 1 to 3 carbon atoms, R17 represents an alkynyl group in the 17~-position or or an acetyl group in the 17~-position, and Z represents X-OH, Y-CO-OH, X-O-CO-Y-CO-OH, ~.~8630S

X-O-CO-R, Y-CO-OR, X-O-CO-Y-CO-OR or X-O-S02-R
in which X represents a straight or branched alkylene group having from 1 to 6 carbon atoms, optionally interrupted by -one or more o- or S-atoms, of which the branched groups and also the terminal groups may be substituted by -OH, -O-CO-R
or -O-S02-R, Y represents a direct bond, a straight or branched -carbon chain optionally interrupted by one or more 0- or S-atoms, the chain having from 1 to 3 carbon atoms when Y is bound through -O-CO- to the steroid residue, or from 1 to 16 carbon atoms when Y is bound through -O-CO- to X, or a 1,4-phenylene, 1,4-cyclohexyl-ene or 1,3-cyclopentylene group or an analogous 1,2-or 1,3-disubstituted group, which may be unsubstituted or substituted by an alkyl group having 1 or 2 carbon atoms, and R represents a hydrocarbon radical having up to 22 carbon atoms, which may be unsubstituted or substituted, non-interrupted or interrupted, and a salt, especially a physiolog-ically tolerable salt, thereof.
~o The steroid molecule may be further substituted in conventional manner. As possible substituents there may be mentioned, for example, etherified and esterified ~- and ~
configurated hydroxyl groups in the 1-, 2-, 3-, 4-, 7-, 11-, 15-and/or 16-positions, keto groups in ~e 3-, 6- and/or ll-positions, saturated and unsaturated aliphatic groups having from 1 to 5 carbon atoms, preferablya methyl or ethyl group, in the 1-, 2-, 4-, 6-, 7- and/or 16-positions, methylene groups in the 1,2-, 6,7- and/or 15,16-positions, halogen atoms, preferably a fluorine or chlorine atom, in the 2-, 4-, 6-, 7-, 9-, 11- and/or 16-positions.
The rings A, B, C and D may be saturated or unsaturated, and double bonds may be present, for example, inthe 1(2)-, 3(4)-, _ 3 _ :, . ... . ..... , , ., ,. ~ , 1~86305 4(5)-, 5(10)-, 5(6)-, 6(7)-, 9(10)-, 9(11)-, 11(12)- and/or 15(16)-positions.
An alkynyl radical in the 17~-position is preferably a lower alkynyl radical and may be, for example, an ethynyl, chlor-ethynyl, propynyl or butadiynyl group, ethynyl being preferred.
The radical represented by X is especially a straight or branched alkylene group having from l to 6 carbon atoms and optionally interrupted by one or more O- or S- atoms, or a cyclo-alkylene group having up to 6 carbon atoms, the branched or terminal chains or rings of X being unsubstituted or substituted ~-by an -OH, -O-CO-R or -O-SO2-R group. For X there may be mentioned for example, the following groups:

2 ' -CH -CH - -CH-CH2-, -CH2-CH2-CH2-~

-CH2-CH2-CH -CH ~ -C- , -CH -CH-CH2- and -CH-CH2-CH2 chains having from 1 to 3 atoms being preferred. -The radical represented by Y is especially a direct carbon-to carbonbond, a straight or branched carbon chain of 1 to 3 atoms optionally interrupted by an O- or S-atom such, for example, as - CIH3 ICH3 C 2 ' -CH2~CH2-, -CH-CH2-, -CH2-CH-~

2 2 CH2 , -CH2-O-CH2- or -CH2-S-cH2 ' or a 1,4-phenylene, 1,4-cyclohexylene or l,3-cyclopentylene group ;
which may be unsubstituted or substituted by an alkyl group having 1 or 2 carbon atoms. ~hen Y is bonded to X through -O-CO-, Y
may also represent a carbon chain having from l to 16 carbon atoms, optionally interrupted by one or more O-, . , , , ,, -, . . . .

1~86305 o~ S- atoms.
The monovalent hydrocarbon radical represented by R
may contain one or more aliphatic, cycloaliphatic, aromatic or heterocyclic groupings and may therefore belong, for example, to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic or heterocyclic series. The hydrocarbon radical may be saturated or unsaturated, unsubstituted or substituted, for example in a conventional manner. As examples of substituents there may be mentioned alkoxy, oxo and amino groups and halogen atoms.
R may contain up to 22 carbon atoms, and preferably from 4 to 18 carbon atoms.
As possible radicals represented by R there may be !~:
mentioned, for example:
alkyl and substituted alkyl groups such, for example, as the methyl, diethylaminomethyl, chloromethyl, ethyl, propyl, isopropy~, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, te.-t.-pentyl, J
2-methylbutyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, pentadecyl, hexadecyl and octadecyl group, cycloalkyl and cycloalkylalkyl groups such, for example, as the cyclopentyl, ~;
cyclohexyl and cyclopentylmethyl group, aryl and aralkyl groups such, for example, as the phenyl, benzyl, 2-phenethyl, to]yl, cinnamyl, ~- or ~-naphthyl group, heterocyclic and heterocyclie-containing groups such, for example, as the pyridyl, piperidyl, pyrrolidinyl, furanyl, piperidinomethyl and morpholinomethyl group, and hydrocarbon groups interrupted by one or more oxygen atoms such, for example, as the 9-methyl-2~5~8-trioxadecyl group; thus COR may be lO-methyl-3,6,9-trioxa-undecanoyl, i.e.
COC~I2OC~l2c~l2Oc~l2cll2ocll(c1~3)2-Preferred depot-steroid esters are compounds of the general formula i~
j~.

' [
... . . . .. ..

` ~0~6305 p o--c--z ~:
`131 ,C-CH

16 (II) ~ '''' . ' .
in which R13 and Z have the meanings given above, the broken lines represent optional further carbon-to-carbon bonds, A represents, `-~
together with adjacent carbon atom or atoms, the grouping Rlo represents a hydrogen atom or a methyl group, ~-R3 represents a hydrogen atom, a lower acyl, alkyl- .
sulphonyl, alkyI or cycloalkyl group, ~-~
W = H2, 0 or H, OR3, represents a double bond in the 4,5-, 5,6- or 5,10-,:
,' " position, and ;
R15 and R16 each represent a hydrogen atom or both ~20 together represent a methylene group in the ~- or ~-position or ;
a further carbon-to-carbon bond between the carbon atoms C15 and 16.
Preferred lower acyl groups R3 are the acetyl, propionyl and butyryl groups. Suitable alkyl groups and alkyl moieties in ~ "
alkylsulphonyl groups are lower alkyl groups and moieties, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert.-butyl. Suitable cycloalkyl groups are those having from

3 to 8 carbon atoms, the cyclopentyl group being preferred.
,.

- ,6 -~ `` 1013630S

Other preferred depot-steroid esters are compounds of the general formula f 3 o Rl ~ O a z R~ ~ (III) ~ 1'~7 in which Rlo, R13 and Z have the meanings given above, Rl and R2 each represent a hydrogen atom or both together represent a methylene group or a further carbon-to-carbon bond between the carbon atoms Cl and C2, ~; R4 represents a hydrogen or a chlorine atom, R6 represents a hydrogen atom, a chlorine atom or a methyl group`and 6----7 represents a single or double bond between the carbon atoms C6 and C7.
The depot-steroid esters of the invention generally produce higher levels of active substance than do the hitherto -known steroid esters. The increase may be up to 800~. The I steroid esters of the present invention generally possess the ~ : , same pharmacological properties as the known corresponding ~;~
steroid alcohols from which they may be prepared. They are especially distinguished by their strong oestrogenic or gestagenic activities.
It is known that a protracting effect can be produced when biologically active steroid alcohols are esterified with long chained, branched or cyclic fatty acids, or biologically active lower esters of steroid alcohols are converted into higher esters.
The length or the branching of the fatty acid is a decisive factor for the desired protracting effect. Thus, for example, a considerable protracting effect may be achieved with 1~ 6305 . , , ' an undecylate, but owing to the strongly decreased splitting of the steroid estex liberated from the depot a considerably - ~
decreased action has to be taken into account. As the hydrolysis -of a tertiary ester, as compared with the metabolisation or direct separation of the ester, proceeds very slowly, it is necessary to administer doses of the long-chained ester that are unsuitably high in order to achieve the therapeutic effect of the alcohol. ;~
We have found that a depot-steroid ester of the inven-tion may be hydrolysed either completely or almost completely and yields correspondingly high levels of active substance, and that the speed of hydrolysis and therewith the duration of action can be controlled by the choise of the radicals X, Y and R in the general formulae I, II and III. -~hereas, usually, after esterification of the tertiary 17-hydroxyl ~roup, receptor-binding of the steroid no longer -occurs in ln vitro tests, in the case of a 17-hydroxy-ester (Z = X-OH) of the invention, for example, the 17-glycollate, there is observed, as compared with the steroid alcohol, a receptor-binding that is decreased to a small extent, e.g. only by a factor of 3 to 4. In this way the desired therapeutic effect may be strengthened, because a pharmacologicaily ætive , compound is present prior tothe splitting of the hydroxy-ester.
The length and structure, especially of the second and optionally the third, ester residue in a compound of the general formula I is a determining factor for the duration of action.
By the esterificationof a 17-OH steroid with a hydroxy- or carboxy-carboxylic acid solubility is increased and in many cases the melting point is simultaneously raised. Thereby a few of the new depot-esters may be administered intramuscularly either in oily solutionor in aqueous microcrystalline suspension.
~; The present invention also provides a process for the l~)B~305 preparation of a depot-ester of the general formula I or a salt thereof, which comprises esterifying a steroid alcohol of the general formula ~ OH

,~
¦ A ¦ B ~ (IV), /\/ ':
, in which A, B, C and D, Rlo, R13 and R17 have the meanings given above.
The esterification may be carried out by a method known per se. For example, the tertiary depot-ester may be formed by esterification with a short-chained hydroxy- or carboxy-carboxylic acid of the general formula HO-X-COOH or HOOC-Y-COOH
to form a hydroxy- or carboxy-carboxylic acid ester of the general formula Q-O-CO-X-OH (V) or Q-O-CO-Y-COOH (VI) where Q represents the steroid residue and X and Y have the meaningS given above.
The hydroxy-carboxylic acid ester (V) may then be further est~ri-fied with a further carboxylic acid of the formula R-COOH, a dicarboxylic acid of the formula HOOC-Y-COOH or sulphonic acid of the formula R-SO2OH to give a compound of the general formula Q-O-CO-X-O-CO-R (VII), Q-O-CO-X-O-CO-Y-COOH (VIII) or Q-O-CO-X-O-SO2R (IX) where Q, X, Y and R have the meanings given above. Esterification of the acids of the general formula VIII
or VI with an alcohol of the general formula ROH leads to a compound of the general formula Q-O-CO-X-O-CO-Y-COOR (X) or Q-O-CO-Y-COOR (XI), respectively, Q, X, Y and R having the meanings given above. Alternatively, esterification of the compound of the general formula IV with the desired acylated hydroxy-carboxylic ; 30 acid of the general formula HOOC-X-O-COR or esterification of the compound of the general formula V or IV with a semi-esterified carboxy-carboxylic acid of the general formula HOOC-Y-COOR, gives ~86305 a product of the general formula VII, X or XI respectively. In this ~ay there are obtained compounds that contain one, two or three ester groups.
Thus, the steroid alcohol IV may be dissolved in an inert solvent and reacted with the desired acid anhydride or halide in the presence of an acid or basic catalyst suitably at a temperature in the range of from 0 to 150 4C . A further possibility consists in reacting the steroid alcohol IV with the free hydroxy-carboxylic acid HOOC-X-OH or one that is esterified at the hydroxyl group HOOC-X-O-COR or with the free or semi-- - esterified dicarboxylic acid HOOC-Y-COOH or HOOC-Y-COOR suitably by treatment with trifluoroacetic anhydride in an inert solvent optionally with the addition of an acid catalyst suitably at a temperature in the range of from 0 to 40 C.
Suitable acid catalysts are for example, para-toluene sulphonic acid, perchloric acid and sulphuric acid; suitable basic catalysts, which may also serve as solvents, are, for example, triethylamine, pyridine and collidine. Any inert solvent may be used as the reaction medium, preferably benzene or a solvent derived from benzene, e.g. toluene or chlorobenzene, or an ether, e.g. diethyl ether, dioxan or tetrahydrofuran, a hydrocarbon, e.g. hexane, a halogenated hydrocarbon, e.g.
methylene chloride, ethylene chloride or chloroform, or a polar solvent, e.g. acetonitrile or dimethyl sulphoxide.
A hydroxy-ester V (Z = XOH) obtained with a hydroxy-fatty acid may be esterified at the free hydroxyl group in the manner usual for primary alcohols. A preferred esterifying agent ;- ~;
is an acid anhydride or halide inthe presence of a basic catalyst. ~
The reaction temperature is suitably in the range of from 0 to -;-lQ0C. The hydroxy-fatty acid may contain 1 to 3, preferably 1, hydroxyl group.

An acyloxy-fatty acid ester VII (Z = X-O-CO-R) thus , i30S

obtained or obtained with an acyloxy-fatty acid may be hydrolysed with a catalytic quantity of a solution of an alkali or alkaline earth metal hydroxide in alcohol at a low temperature, suitably in the range of from 0 to 50C and a short reaction time, suitably of from one minute to 3 hours. The reaction mixture may also contain an inert solvent or diluent, e.g. methylene chloride, diethyl ether or tetrahydrofuran. After the hydrolysis, if desired esterification in the second stage may be carried out with the desired carboxylic or sulphonic acid (R-COOH or R-SO2OH) or dicarboxylic acid (HOOC-Y-COOH).
The optional subsequent esterification of the free ~ ;
carboxy group of the primarily formed semi-ester VI (Z = Y-CO-OH) may also be carried out by a method known per se. Thus, the semi-ester may be reacted, for example, with diazomethane or diazoethane and the corresponding methyl or ethyl ester obtained. A method of general application is reaction of the semi-ester with the alcohol in the presence of carbonyl-diimidazole, dicyclohexyl-carbodiimide or trifluoroacetic anhydride. It is also possible to convert the acid into its silver salt and react the latter with an R-halide. A further method consists in convert-ing the semi-ester having a free carboxyl group with the corres-ponding dimethylformamide-alkyl-acetal into the corresponding ;
alkyl ester. Furthermore, the semi-ester may be reacted in the presence of a strongly acid catalyst, e.g. hydrochloric acid, sulphuric acid, perchloric acid, trimethyl-sulphonic acid or para-toluene sulphonic acid, with an alcohol or lower alkane carboxylic acid ester of the alcohol. However, it is also possible to convert the carboxyl group of the semi-ester into the acid chloride or anhydride and then to react with the alcohol in the presence of a basic catalyst.
It is often advantageous to prepare first in one step a ~86305 hydroxy- or carboxy-ester esterified with a lower fatty acid or with a lower alcohol, then to hydrolyse to form the free hydroxy-or carboxy-ester, and only in the last step to esterify with the acid or alcohol of the desired chain length.
A 17-glycollic acid ester may also be prepared, for ~
example, in the following manner: ` -A 17-crotonic acid ester is first prepared with crotonic acid in the presence of trifluoroacetic anhydride. After the --protection of optionally present ketone groups, for example in the 3- or 3,20-position, preferably by ketalisation, oxidation is carried out with potassium permanganate in the presence of formic acid at a temperature around the freezing point of water to form the 2,3-dihydroxybutyric acid ester. By oxidative- ~;
splitting with periodate at a temperature from 0 to 50C, the 17-glyoxalic acid ester is obtained, which by reduction is changed in the desired glycollic acid ester. The oxidation ; with permanganate and the oxidative splitting with periodate are carried out in aqueous inert solvents, such, for example as -~
acetone, tetrahydrofuran or dioxan. The reduction may be carried out in the usual manner with an alkali metal boranate or lithium tri-tert.-butyoxy-alanate. Depending on the desired end product, optionally present protected keto groups may be liberated directly or after esterification of the hydroxyl group of the glycollic ~ acid ester. ;
; This invention also provides a pharmaceutical prepara-tion, especially a depot-preparation, which comprises a steroid ester of the general formula I or a physiologically tolerable salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier. Suitably the preparation is in dosage unit form.
The gestagenically or oestrogenically active steroid esters are suitable, for example, for the control of fertility in human beings and animals (especially as a contraceptive) or for the treatment of menopausal .. . . ..

~86305 complaints in women. There may also be used combinations of, for example, gestagenic and oestrogenic or oestrogenic and androgenic steroid esters.
The effective dose depends on the purpose of the treat-ment, the nature of the active substance and the desired duration ~-of action. The effective dose of, for example 17~-ethynyl-18-methyl-17~-(0-undecanoyl-glycoloyloxy)-4-oestren-3-one for the control of fertility in women is thought to be from 10 to 50 mg for 3 months and the quantity of other gestagenically active steroid esters administered is the same as that which corresponds to the administration of 3-monthly 10 to 50 mg of 17~-ethynyl-18-methyl-17~-(0-undecanoyl-glycoloyloxy)-4-oestren-3-one.
A preparation of the present invention may be administered perorally or by implantation or injected subcutaneously or injected intramuscularly in oily solution or in aqueous crystal suspension. -`~
The injection volume is, for example, from 1 to 4, preferably 1 to 2 ml.
For preparing an oily solution the steroid ester may be -dissolved in a solvent or solvent mixture suitable for the injec-tion, filtered sterile and charged into ampoules under aseptic conditions. ;
Suitably oily solvents are, for example, sesame oil and castor oil. For increasing the solubility of the active substance, ,~
solubilizers such, for example, as benzyl benzoate or benzyl alcohol, may be added to the oily solvent. Besides those already mentioned, there may be used other vegetable oils e.g. linseed oil, cotton seed oil, sunflower oil, ground-nut oil, olive oil ~
and wheat oil. Also suitable are synthetic oils, e.g. polyethylene ~ -glycol, triglycerides of higher saturated fatty acids and mono-esters of higher fatty acids. As a solvent mixture, a mixture of castor oil/benzyl benzoate in the ratio of 6:4 is preferred.

The following Examples illustrate the invention.

.. . ..

1~36305 Example 1 To 30.9 grams of crotonic acid in 800 ml of benzene are added 48.1 ml of trifluoracetic anhydride, and the mixture is stirred for 30 minutes at room temperature. 50 Grams of 17~-ethynyl-17~-hydroxy-18-methyl-4-oestren-3-one axe then added and the whole is stirred for 30 minutes at room temperature. The reaction solution is diluted with ether, washed with water and sodium hydrogen carbonate solution, dried and evaporated. For enol-ester splitting the residue is taken up in 1.3 litres of methanol, 130 ml of sulphuric acid of 8~ strength by volume are added, and the whole is heated under reflux for 2 hours. After precipitation in ice-water, the precipitate is filtered off, washed with water, taken up in methylene chloride and dried. The -residue obtained after evaporation is recrystallised from diisopropyl ether/acetone, and 43.3 grams of 17~-ethynyl-17~-! crotonoyloxy-18-methyl-4-oestren-3-one melting at 187-188C. are obtained.
211 18700; E238 = 18100.
To 45 grams of 17~-ethynyl-17~-crotonoyloxy-18-methyl-4-oestren-3-one in 450 ml of methylene chloride are added 90 ml of ortho-formic acid tiethyl ester, 112 grams of 2,2-dimethyl-1,3-propandiol and 450 mg of para-toluene sulphonic acid, and the whole is stirred for 60 minutes at a bath temperature of 50~C. The mixture is then diluted with ether, washed with sodium hydrogen carbonate solution and water, dried and evaporated.
The residue is chromatographed over silic gel, and 39.5 grams of 17a-ethynyl-17~-crotonoyloxy-3,3(2,2-dimethyl-trimethylenedioxy)-18-methyl-5- and 5(10)-oestrene are obtained in the form of an oil.
40 Grams of 17~-ethynyl-17~-crotonoyloxy-3,3(2,2-dimethyl-trimethylenedioxy)-18-methyl-5- and 5(10)-oestrene are dissolved in 1.5 litres of acetone, the solution is cooled in an ' ~36305 ice bath, 11.2 ml of formic acid of 100% strength are added, and in the course of 2 hours a solution of 23.7 grams of potassium permanganate in 395 ml of waterand 3.3 litres of acetone is added. The mixture is thenfurther stirred for 30 minutes at 0C., 1 litre of methylene chloride is added and precipitated pyrolusite is filtered off. The filtrate is concentrated to a great extent in vacuo, the residue is taken up in ether, and the mixture is washed with water, dried and evaporated. By chromatography over silica gel there are obtained, in addition to 12 grams of unreacted starting material, 30.2 grams of 17~-ethynyl-17~(2,3-dihydroxy-butyroxy)-3,3(2,2-dimethyl-trimethylenedioxy)-18-methyl-5- and 5(10)-oestrene in the form of an oil.
To 30 grams of 17~-ethynyl-17~(2,3-dihydroxy-butroxy)-3,3(2,2-dimethyl-trimethylenedioxy)-18-methyl-5- and 5(10)-oestrene in 1.5 litres of dioxane are added 89.6 grams of sodium periodate in 450 ml of water, and the mixture is stirred - ~-for one hour at room temperature. The mixture is then stirred into ice-water, extracted with methylene chloride, washed with water and dried. By evaporation 28.5 grams of crude 17~-ethynyl-3,3(2,2~imethyl-trimethylenedioxy)-17~-glyoxoyloxy-18-methyl-5- and 5(10)-oestrene are obtained.
To 32.5 grams of crude 17~-ethynyl-3,3(2,2-dimethyl-trimethylenedioxy)-17~-glyoxoyloxy-18-methyl-5- and 5(10)-oestrene in 995 ml of methanol and 142.5 ml of water are added in portions while cooling with ice 6.5 grams of sodium boranate.
The mixture is then stirred for 10 minutes at ice bath temperature and stirred into ice-water. The precipitate phase acidified with 2N-sulphuric acid is extracted with ether, washed with water and dried. The residue obtained after evaporation is chromato-graphedover silica gel, and 30.5 grams of 17~-ethynyl-3,3(2,2-dimethyl~rimethylenedioxy)-17~-glycoloyloxy-18-methyl-5- and - . .~ . .,; . , ~
..

;30S

5(10)-oestrene are obtained. A test portion recrystallised from diisopropyl ether melts at 215.5-219C.
200 mg of 17a-ethynyl-3,3~2,2-dimethyl-trimethylenedioxy)-17~-glycoloyloxy-18-methyl-5- and 5(10)-oestrene in 2 ml of pyridine are allowed to stand with l ml of propionic anhydride for 3 hours at room temperature. The mixture is then stirred in ice-water, the precipitate is filtered off, taken up in ether, washed with water and sodium hydrogen carbonate solution and dried. By evaporation 240 mg of crude 17a-ethynyl-3,3~2,2-dimethyi-~imethylenedioxy)-18-methyl-17~-(O-propionylglycoloyloxy) -5- and 5(10)-oestrene are obtained.
240 mg of crude 17a-ethynyl-3,3(2,2-dimethyl-trimethyl- -enedioxy)-18-methyl-17~-(O-propionyl-glycoloyloxy)-5- and 5(10)-oestrene in 6 ml of methanol and 1.2 ml of water are heated under reflux for one hour with 120 mg of oxalic acid.
The mixture is diluted with ether, washed with water and dried.
After evaporation the residue is chromatographed over silica gel, and by recrystallisation from diisopropyl ether 100 mg of 17a-ethynyl-18-methyl-17~-(O-propionyl-glycoloyloxy)-4-oestren-3- ;~
one melting at 125-126C. are obtained.
W: 240 = 17500- ~
Example 2 ;~-

4.0 Grams of 17a-ethynyl-3,3(2,2-dimethyl-trimethylene-dioxy)-17~-glycoloyloxy-18-methyl-5- and 5(10)-oestrene in 12 ml of pyridine and 8 ml of oenanthic anhydride are allowed to stand for 20 hours at room temperature. The mixture is then distilled with steam, and the residue is taken up in methylene chloride and dried. After evaporation, chromatography over silica gel is carried out, and 3.8 grams of 17a-ethynyl-3,3(2,2-dimethyl-trimethylenedioxy)-17~-(O-heptanoyl-glycoloyloxy)-18-methyl-5-and 5(10)-oestrene are obtained.

1~6305 3.8 Grams of 17~-ethynyl-3,3(2,2-dimethyl-trimethylene-dioxy)-17~-(0-heptanoyl-glycoloyloxy)-18-methyl-5- and 5(10)-oestrene in 95 ml of methanol and 19 ml of water are heated under reflux with 1.9 grams of oxalic acid for 90 minutes.
The mixture is then stirred into ice-water, the pxecipitate is filtered off, taken up in ether, washed with water and dried.
After evaporation, chromatography over silica gel is carried ~
out, and there are obtained 2.0 grams of 17~-ethynyl-17~-(O- --heptanoyl-glycoloyloxy)-18-methyl-4-oestren-3-one melting at ;
90-9lQC.
UV E240 = 17000-Example 3 To 4.0 grams of 17~-ethynyl-3,3-(2,2-dimethyl-trimethyl- ` ~-~
enedioxy)-17~-glycoloyloxy-18-methyl-5- and 5(10)-oestrene in ~, 12 ml of pyridine are added at ice bath temperature 4 ml of ~
undecanoic acid chloride, and the mixture is allowed to stand ~ --for 20 hours at room temperature. By working up and purifying - -in a manner analogous to that in Example 2 3.9 grams of -17~-ethynyl-3,3-(2,2-dimethyl-trimethylenedioxy)-18-methyl-17~-~(O-undecanoyl-glycoloyloxy)-5- and 5(10)-oestrene are obtained. , 3.9 Grams of 17~-ethynyl-3,3-(2,2-dimethyl-trimethylene-dioxy)-18-methyl-17~-(O-undecanoyl-glycoloyloxy)-5- and 5(10)-oestrene in 95 ml of methanol and 19.5 ml of water are heated under reflux with 1.95 grams of oxalic acid for 90 minutes.
By working up and purifying in a manner analogous to that in Example 2 there are obtained 2.0 grams of 17~-ethynyl-18-methyl-17~-(O-undecanoyl-glycoloyloxy)-4-oestren-3-one as an oil.
UV: 240 - 17000.
Example 4 1.3 Grams of 17~-ethynyl-3,3-(2,2-dimethyl-trimethylene-dioxy)-17~-glycoloyloxy-18-methyl-5- and 5(10)~oestrene in 39 ml '~

- 17 - ~;

63(~5 of methanol are stirred with 3.9 ml of sulphuric acid of 8~ -~
strength by volume for 3 hours at room temperature. The mixture is then diluted with ether, washed with water and dried. After evaporation the residue is chromatographed over silica gel, and ~`
by recrystallisation from diisopropyl ether 620 mg of 17~-ethynyl- - -17~-glycoloyloxy-18-methyl-4-oestren-3-one melting at 158.5-159.5C. are obtained.
UV: ~240 = 17600-Example 5 100 mg of 17~-ethynyl-17~-glycoloyloxy-18-methyl-4-oestren-3-one are dissolved in 1 ml of pyridine and 160 mg of 3-cyclopentyl-propionyl chloride are added while cooling. The mixture is allowed to stand for 24 hours at room temperature, stirred into ice-water, taken up with ether, washed neutral and :
chromatographed, after drying and concentrating, over silica gel. 110 mg of 17~-ethynyl-17~-~0-(3-cyclopentylpropionyl)- ; ;
glycoloyloxy]-18-methyl-4-oestren-3-one are obtained. -~
In a manner analogous to that in Example 5 there are prepared:
17~-Ethynyl-17~-(O-tridecanoyl-glycoloyloxy)-4-oestren-3-one, 17~-ethynyl-17~-(O-hexadecanoyl-glycoloyloxy)-4-oestren-3-one, ;
17~-ethynyl-17~-(O-octadecanoyl-glycoloyloxy)-4-oestren-3-one, 17~-Ethynyl-17~-(O-tridecanoyl-glycoloyloxy)-18-methyl-4-oestren-3-one and 17a-ethynyl-17~(0-tridecanoyl-glycoloyloxy)-18-methyl-4,15- -oestradien-3-one.
Example 6 -500 mg of 17~-ethynyl-17~-hydroxy-18-methyl-4-oestren-3-one are dissolved in 5 ml of collidine (freshly distilled) and 180 mg of 4-dimethylamino-pyridine and 1.25 grams of 2-nonanoyl-oxy-propionyl chloride are added while cooling with ice. The mixture is heated under nitrogen for 24 hours at 110C. The 1~363US
reaction mixture is taken up with ether and washed neutral with an aqueous solution of oxalic acid and water. After drying the ether and concentrating in vacuo, chromatography over silica gel is carried out, and 17~-ethynyl-17~-(2-nonanoyloxy-propionoxy)-18-methyl-4-oestren-3-one is obtained.
Example 7 (a) 1 Gram of 3-acetoxy-propionic acid are stirred in 21 ml of benzene with 1.05 ml oftrifluoracetic anhydride for one hour at room temperature. While cooling and gasing with nitrogen 0.99 gram of 17~-ethynyl-17~-hydroxy-18-methyl-4-oestren-3-one is added, and the mixture is stirred for 24 hours.
The reaction solution is decomposed with methanol/water and washed neutral with water, sodium hydrogen carbonate solution and again with water. The benzene solution is dried with sodium sulphate and concentrated ln vacuo. The oily residue is chromato-graphed over silica gel, and 650 mg of 17~-(3-acetoxy-propionoxy)-17~-ethynyl-18-methyl-4-oestren-3-one are obtained.
UV: ~240 = 17200-(b) 250 mg of 17~-(3-acetoxy-propionoxy)-17~-ethynyl-~ ~, 18-methyl-4-oestren-3-one are dissolved in 2 ml of methylene chloride and 2 ml of methanol, and an ethanolic solution of potas-sium hydroxide is added at 5C under nitrogen. After 2 hours the ~ -~
mixture is neutralised with glacial acetic acid and stirred into -ice-water. The precipitated product is filtered off with suction and dried. By chromatography over silica gel and recrystallisa-tion from diisopropyl ether 200 mg of 17~-ethynyl-17~-(3-hydroxy-propionoxy)-18-methyl-4-oestren-3-one melting at 159-160C are ;
obtained.
UV: ~240 = 16400-Example 8 (a) 1 ~ram of malonic acid monoethyl ester is stirred in 20 ml of dry benzene with 1 ml of trifluoracetic anhydride 1~3630S

for one hour at room temperature under nitrogen. 0.93 gram of 17~-ethynyl-17~-hydroxy-18-methyl-4-oestren-3-one is then added and the whole is allowed to stand for 36 hours at room temperature.
Af~ter the addition of methanol and ether the mixture is washed neutral and concentrated. By chromatography over silica gel there are obtained 550 mg of 17~-ethynyl-17~-(ethoxy-malonyloxy)-18-methyl-4-oestren-3-one melting at 75-95C. (the spontaneously crystallising substance is triturated with hexane and dried in a high vacuum), UV: 240 = 17300-(b) 100 mg of 17~-ethynyl-17~-(ethoxy-malonyloxy)-18- ~-methyl-4-oestren-3~one are dissolved in 1 gram of dodecyl alcohol and 5 ml of benzene at 40C, and 5 mg of potassium tert.-butylate are added under nitrogen. After one hour the excess of alcohol is removed in a high vacuum, the residue is neutralised with acetic acid, and chromatography over silica gel is carried out. 120 mg of 17~-ethynyl-17~-(dodecyloxy-malonyloxy)-18-methyl-4-oestren-3-one are obtained.
W: 240 = 16100.
-E~ample- 9 1 Gram of 17a-ethynyl-17~-hydroxy-4-oestren-3-one is dissolved in 10 ml of collidine, the solution is cooled to 0C, and 1.3 ml of ethoxyoxalyl chloride are added while gassing with nitrogen. The mixture is allowed to stand for 1 hour at room temperature and stirred into aqueous oxalic acid solution, and the precipitated product is filtered off with suction, washed with water and dried. By chromatography over silica gel 770 mg of ~ -17~-ethynyl-17~-(ethoxy-oxalyloxy)-4-oestren-3-one melting at 89-90C. are obtained.
UV 240 = 17000 ., .~ :

1~36305 EXample 10 100 mg of 17~-ethynyl-17~-(ethoxy-oxalyloxy)-4-oestren-3-one are dissolved in 10 ml of benzene and 500 mg of butanol are added. 5 mg of potassium tert.-butylate are added at room temperature and the mixture is stirred. After the addition of acetic acid the benzene is removed, and the residue is chromatographed over silica gel. 120 mg of 17~-ethynyl-17~-(butoxy-oxalyloxy)-4-oestren-3-one are obtained~

EXample 11 :' 50 mg of 17~-ethynyl-17~-glycoloyloxy-4-oestren-3-one are dissolved in 0.5 ml of dry pyridine and 0.11 gram of 3,6,9-trioxa-isododecanoyl chloride is added while cooling with ice. The whole is allowed to stand for 24 hours at room temper-ature under nitrogen, taken up in ether, washed with an aqueous solution of oxalic acid, the ether phase is dried and concentrated. ;~
By chromatography over silica gel there are obtained 64 mg of 17~-ethynyl-17~-(O-10-methyl-3,6,9-trioxaundecanoyl-glycoloyloxy)- ~-4-oestren-3-one.
Example 12 ~ -1 Gram of 17~-ethynyl-17~-hydroxy-4-oestren-3-one is dissolved in 10 ml of collidine (freshly distilled) and 250 mg of 4-dimethylamino-pyridine are added. After cooling to +5C., 0.65 ml of acetoxy-glycoloyl chloride is added dropwise, and the whole is slowly heated to 100C while gassing with nitrogen.
After 1 hour the mixture is cooled, and a further 0.65 ml of acetoxy-glycoloyl chloride is added. The mixture is then heated for 3 hours at 100C. After being cooled, the mixture is taken up in ether, washed neutral with oxalic acid solution and then with water, dried and evaporated. By chromatography over silica gel there are obtained 800 mg of 17~-(O-acetyl-glycoloyloxy)-17~-ethynyl-4-oestxen-3-one melting at 179-180C. (from diisopropyl ether).

- .

~086305 Exa~ple 13 500 mg of 17~-(O-acetyl-glycoloyl)-17~-ethynyl-4-oestren-3-one are dissolved in methylene chloride/methanol (1:1), the solution is cooled to 5C. and an ethanolic solution of potassium hydroxide is added under nitrogen. After 15 minutes, the mixture is neutralised with acetic acid, stirred into ice-water and the precipitated product is filtered off with suction.
By chromatography over silica gel 420 mg of 17a-ethynyl-17~-glycoloyloxy-4-oestren-3-one melting at 207-210C. are obtained.
W ~240 = 17000.
Examp-le 14 100 mg of 17a-ethynyl-17~-glycoloyloxy-4-oestren-3-one are dissolved in 1 ml of dry pyridine and, while cooling with ice and under nitrogen, 350 mg of 0-(4-octyloxy-benzoyl) glycoleyl chloride are added. The mixture is allowed to stand for 24 hours -`
at room temperature, taken up with ether, washed with oxalic acid solution and water, and the ethereal phase is dried. By concentrating in vacuo and chromatography of the residue over silica gel 120 mg of 17~-ethynyl-17~-IO-(4-octyloxy-benzoyl)-glycoloyloxy~-4-oestren-3-one are obtained.
Example 15 `! ~
100 mg of 17~-ethynyl-17~-glycoloyloxy-4-oestren-3-one are dissolved in 1 ml of dry pyridine, and, while cooling with ice and under nitrogen, 0.5 ml of O-(4-octyloxycarbonyl-cyclohexylcarbonyl)-glycoloyl chloride is added. After allowing the mixture to stand for 24 hours at room temperature, it is -~ diluted with ether, washed with an aqueous solution of oxalic acid and then washed neutral with water. After drying the ether and concentrating in V~cuo the residue is chromatographed over 30 silica gel. 135 mg of 17~-ethynyl-17~-(0-[4-octyloxycarbonyl-cyclohexylcarbonyl]-glycoloyloxy)-4-oestren-3-one are obtained.

: - . ,, .; . :. . . .. ,~ . ..... .

10863(~S

Example 16 To 10 ml of dimethyl sulphoxide are added 1.48 ml of diglycollic acid monomethyl ester and, while cooling, 1.5 ml of trifluoracetic anhydride are added dropwise. After one hour 1 gram of 17~-ethynyl-17~-hydroxy-4-oestren-3-one is added. The whole is allowed to stand for 24 hours under nitrogen at room temperature, poured into ice-water and extracted with ether. After drying and concentrating, chromatography over silica gel is carried out, and 430 mg of 17~-ethynyl-17~-(O-meth-oxycarbonylmethyl-glycoloyloxy)-4-oestren-3-one melting at 125-132C. (from diisopropyl ether~ are obtained.
UV: ~240 = 17200.
Example 17 100 mg of 17~-ethynyl-17~-(O-methoxycarbonylmethyl-glycoloyloxy)-4-oestren-3-one are dissolved in 1 ml of decanol,

5 mg of potassium tert.-butylate are added, and the mixture is - -allowed to stand for one hour at room temperature. Acetic acid ~ -is added, the alcohol is removed in a high vacuum, and the residue is chromatographed over silica gel. 115 mg of 17~-ethynyl-17~-(O-decyloxycarbonylmethyl-glycoloyloxy)-4-oestren-3-one are obtained.
Example 18 500 mg of 17~-ethynyl-17~-hydroxy-4-oestren-3-one are dissolved in 5 ml of freshly distilled collidine and, while cooling with ice and under nitrogen, 180 mg of 4-dimethylamino-pyridine and 2.1 grams of 4-undecanoyloxy-cyclohexane-carbonyl chloride are added. The mixture is heated for 3 hours at 100C., after cooling and adding 2 ml of collidine a further 0.75 ml of the acid chloride is added, and the whole is heated for a further

6 hours at 100C. After working up with ether and an aqueous solution of oxalic acid, drying and concentrating, 600 mg of crude substance remain behind. By chromatography over silica gel ~C~E363~S

there are obtained 330 mg of 17~-ethynyl-17~-(4-undecanoyloxy-cyclohexylcarbonyloxy)-4-oestren-3-one.
Example 19 :
(a) 200 mg of 17~-ethynyl-17~-hydroxy-4-oestrene are dissolved in 2 ml of freshly distilled collidine and, while cooling with ice and gassing with nitrogen, 400 mg of acetoxy-glycoloyl chloride are added. The mixture is heated for 3 hours at 60C, and, after cooling, there are added 200 mg of 4-dimethyl-amino-pyridine and a further 400 mg of the acid chloride. The reaction mixture is maintained at 60C. for a further 10 hours.
After cooling, the mixture is diluted with ether, washed with an aqueous solution of oxalic acid and water, and the ether is dried.
By chromatography over silica gel 170 mg of 17~-(O-acetyl-glycoloy-loxy)-17~-ethynyl-4-oestrene are obtained.
(b) 50 mg of 17~-(O-acetyl-glycoloyloxy)-17~-ethynyl-4-oestrene are dissolved in 1 ml of methylene chloride and 0.5 ml of methanol, the mixture is cooled to 5C, gassed with nitrogen and 0.5 ml of an ethanolic solution of potassium hydroxide of 3%
strength is added. After 15 minutes the mixture is neutralised with acetic acid, taken up in ether and washed neutral. By chromatography over silica gel 35 mg of 17~-ethynyl-17~-glycoloyl- `
oxy-4-oestxene are obtained.
Example 20 : ~, 15 mg of 17~-ethynyl-17~-glycoloyloxy-4-oestrene are dissolved in 0.2 ml of dry pyridine and, while coollng, 100 mg of stearoyl chloride are added. The whole is allowed to stand for 24 hours. The mixture is then distilled with steam and the residue is taken up in ether, it is separated on analytical thin layer plates, the desired rapidly running product is rendered visible with primuline and eluted. 17 mg of 17~-ethynyl-17~-(O-steaxoyl-glycoloyloxy)-- 4-oestrene are obtained.

, ~ - , ~ . . . ; ~

~08630S

Example 21 500 mg of 17~-ethynyl-17~-hydroxy-5tlO)-oestren-3-one '~
are dissolved in 10 ml of freshly distilled collidine, and 250 mg a ~
~`~ ~ of 4-dimethy ~pyridine are added. After cooling to 5C., 4 grams ' of O-undecanoyl-glycoloyl chloride are added and the whole is '~
heated for one hour at 100C. The mixture is cooled, ether and an ice-cooled aqueous solution of oxalic acid are added, washed ' neutral with water, the ethereal phase is dried and chromatographed with chlorine- and chloride-free methylene chloride over neutral silica gel washed with methanol. A mixture of 370 mg of 17~-ethynyl-17~-tO-undecanoyl-glycoloyloxy)-5(10)-oestren-3-one and 17a-ethynyl-17~-(O-undecanoyl-glycoloyloxy)-4-oestren-3-one is obtained.
Ex'ample 22 500 mg of 17~-ethynyl-3-methoxy-1,3,5(10)-oestratrien- ' '~
17~-ol are reacted in a manner analogous to that in Example 12 -with acetoxy-glycoloyl chloride. 370 mg of 17~-(O-acetyl-glycoloyl-oxy)-17~-ethynyl-3-methoxy-1,3,5(10)-oestratriene melting at 118-120C. (from ethanol) are obtained.
Example 23 150 mg of 17~-(O-acetyl-glycoloyloxy)-17~-ethynyl-3-methoxy-1,3,5(10)-oestratriene are reacted in a manner analogous to that in Example 13 with ethanolic potassium hydroxide. 110 mg of 17~-ethynyl-17~-glycoloyloxy-3-methoxy-1,3,5(10)-oestratriene melting at 133-135C (from diisopropyl ether) are obtained.
Example 24 50 mg of 17~-ethynyl-17~-glycoloyloxy-3-methoxy-1,3,5(10)-oestratriene are dissolved in 1 ml of dry pyridine and 120 mg of isovaleryl chloride are added. The mixture is allowed to stand for 24 hours, taken up with an aqueous oxalic acid solution and ether, washed neutral with water, and the ethereal phase is dried and concentrated. By chromatography over analytical thin layer plates 55 mg of 17~-ethynyl-17~-(O-isovaleryl-glycoloyloxy)-3-~0863~X

methoxy-1,3,5(10)-oestratriene are obtained.
Example-25 500 mg of 17~-ethynyl-17~-hydroxy-1,3,5(10~-oestratrien-3-ol are dissolved in 5 ml of dry collidine, 180 mg of 4-dimethyl-amino-pyridine are added and, while cooling with ice and under nitrogen, 2.2 grams of O-undecanoyl-glycoloyl chloride are added. The mixture is heated for 3 hours at 70C., stirred into ;
aqueous oxalic acid solution, taken up with ether, and agitated~
for 30 minutes with an excess of an aqueous solution of sodium hydrogen carbonate at 10C. After washing, drying and concentra-ting the etheral phase, chromatography over silica gel is carried out. 420 mg of 17~-ethynyl-17~-(O-undecanoyl-glycoloyloxy)-1,3,5 (10)-oestratrien-3-ol are obtained.
Example 26 200 mg of 17~-ethynyl-3-cyclopentyloxy-17~-hydroxy-1,3, ;-5(10)-oestratriene are dissolved in 2 ml of dry collidine, and, while cooling with ice and under nitrogen, 100 mg of 4-dimethyl-amino-pyridine and 650 mg of O-undecanoyl-glycoloyl chloride are added and the whole is heated for 3 hours at 70C. After cooling, 122 mg of 4-dimethylamino-pyridine are added, and then a further 1 ml of collidine and 650 mg of the acid chloride are added. The mixture is again heated for 12 hours at 80C. After cooling, taking up in ether and washing neutral with aqueous oxalic acid solution and water are carried out. After drying and concentrating, the oily residue is chromatographed over silica gel. 95 mg of 17~-ethynyl-3-cyclopentyloxy-17~-(O-undecanoyl-glycoloyloxy)-1,3, 5(10)-oestratriene are obtained in the form of a colourless oil.
Example 27 250 mg of 17~-ethynyl-17~-hydroxy-3-(propan-2-sulphonyl-oxy)-1,3,5(10)-oestratriene are dissolved in 2.5 ml of dry colli-dine, and, while cooling with ice and under nitrogen, 125 mg of '1~8630S

4-dimethylamino-pyridine and 900 mg of O-valeryl-glycoloyl chloride are added. The mixture is heated for 6 hours at 90C., and, after cooling, taking up in ether is carried out. Af~ter washing and drying, the ethereal phase is concentrated and the oily residue is chromatographed over silica gel. 190 mg of 17~-ethynyl-3-(isopropylsulphonyloxy)-17~-(O-valeryl-glycoloyloxy)-1,3,5(10)-oestratriene are obtained.
Example 28 100 mg of 17~-ethynyl-17~-glycoloyloxy-4-oestren-3-one are dissolved in 1 ml of a mixture of benzene and triethylamine.
While stirring, there is added to this solution at room temperature ~ ~
0.15 ml of isopropyl sulphonyl chloride. The reaction mixture ' is allowed to stand for 16 hours, poured onto ice and, after ;
decomposition of the excess of acid chloride, taking up in ether is carried out. The mixture is washed neutral, concentrated ln ;
vacuo, and the residue is taken up in benzene and filtered over silica gel. 120 mg of 17~-ethynyl-17~-(O-isopropyl-sulphonyl-glycoloyloxy)-4-oestren-3-one are obtained.
Example 29 500 mg of 17~-ethynyl-17~-hydroxy-4-androsten-3-one ~ -are dissolved in 5 ml of collidine and reacted with O-undecanoyl-glycoloyl chloride in the manner analogous to that in Example 26.
370 mg of 17~-ethynyl-17~-(O-undecanoyl-glycoloyloxy)-4-androsten-3-one are obtained.
Example 30 250 mg of 3~-acetoxy-17~-ethynyl-17~-hydroxy-4-oestrene are dissolved in 2.5 ml of dry collidine and reacted with O-; undecanoyl-glycoloyl chloride in a manner analogous to that in Example 26. 160 mg of 3~-acetoxy-17~-ethynyl-17~-(O-undecanoyl-3Q glycoloyloxy)-4-oestrene are obtained.
Example 31 500 mg of 17~-(O-acetyl-gIycoloyloxy)-17~-ethynyl-4-oestren-3-one are dissolved in 15 ml of dioxane. 1 ml of ortho-formic acid ethyl ester and 1.2 grams of para-toluene sulphonic acid are added and the whole is stirred for 6 hours at room temperature. 0.5 ml of pyridine is then added, and the product is precipitated in ice-water and filtered off with suction. The crude product is dissolved in benzene and filtered over a small amount of silica gel. The dienol ether (3-ethoxy-3,5-diene) so obtained is introduced into a boiling solution of 50 ml of benzene, 0.5 ml of cyclopentanol and 10 mg of para-toluene sulphonic acid.
In the course of 30 minutes 5 ml of the solution are distilled off, and 0.15 ml of pyridine is added to the hot solution. After --caoling, concentration ln vacuo is carried out, the residue is taken up in methylene chloride, a small amount of methanol is added and the mixture is concentrated in vacuo. 125 mg of 17~-(O-acetyl-glycoloyloxy)-17~-ethynyl-3-cyclopentyloxy-3,5-oestradiene - ~-melting at 143-156C. are obtained.
Example 32 ~;
500 mg of 17~-ethynyl-17~-hydroxy-18-ethyl-4-oestren-3-one are introduced under nitrogen into a solution of 1 gram of 3-methoxy-undecandioyloxy-propionic acid and 310 mg of trifluor- -acet~c anhydride in 10 ml of benzene. After being allowed to stand for 24 hours at room temperature, 1 ml of methanol is added to the solution, and it is concentrated in vacuo. By chromatography over silica gel there are obtained 280 mg of 17~-ethynyl-18-ethyl-17~-~3-(methoxyundecandioyloxy)-propionoxy]-4-oestren-3-one.
Example 33 500 mg of 17~-ethynyl-17~-hydroxy-18-methyl-15~,16~-methylene-4-oestren-3-one are reacted with crotonic acid and ;

treated in a manner analogous to that in Example 1. 260 mg of 17~-(O-propionyl-glycoloyloxy)-17~-ethynyl-18-methyl-15~,16~-methylene-4-oestren-3-one are obtained.

.. ..

10863~5 Example 34 500 mg of 17~-ethynyl-17~-hydroxy-18-methyl-15~,16~-methylene-4-oestren-3-one are'reacted with crotonic acid and treated as described in Example 1. 370 mg of 17~-(O-propionyl-glycoloyloxy)-17~-ethynyl-18-methyl-15~,16~-methylene-4-oestren-3-one are obtained.
Example 35 725 mg of 4-acetoxy-butyric acid are dissolved in 20 ml of benzene, and 5 ml of benzene are distilled off. After the addition of 1.1 gram of trifluoracetic anhydride, the mixture is stirred for one hour at room temperature. 1 Gram of 4,6-dichloro-17-hydroxy-1~,2~-methylene-4,6-pregnadien-3,20-dione is added under nitrogen, and the whole is stirred for 36 hours at room temperature. The reaction solution is decomposed with -methanol and concentrated in vacuo. The residue is chromatographed ~' over silica gel. 470 mg of 17-(4-acetoxy-butyroxy-4,6-dichloro-1~,2~-methylene-4,6-pregandien-3,20'-dione are obtained.
Examp-le 36 ~
250 mg of 17~-ethynyl-17~-hydroxy-4,9(10),11(12)- ' oestratrien-3-one are reacted with 3-acetoxy-propionic acid in a manner analogous to that in Example 7. 110 mg of 17~-(3-acetoxy-propionoxy)-17~-ethynyl-4,9(10),11(12)-oestratrien-3-one are obtained.
Example 37 ~-250 mg of 17~-ethynyl-17~-hydroxy-18-methyl-4,9(10),11(12) -oestratrien-3-one are reacted with ethoxyoxalyl chloride in ~ -a manner analogous to that in Example 9. 190 mg of 17~-ethynyl-17~-(ethoxy-oxalyloxy)-18-methyl-4,9(10), 11(12)-oestratrien-3-one are obtained.
Example 38 1.6 Grams of malonic acid mono-ethyl ester are dissolved ;~
in 10 ml of benzene and some of the benzene is distilled off ~363~5 ....

under nitrogen. After cooling to room temperature, 1.27 grams of trifluoracetic anhydride are added, and the mixture is further stirred for 30 minutes at room temperature. While cooling with ice, 1 gram of 17-hydroxy-4-pregnen-3,20-dione is then added.
After stirring overnightthe reactionsolution is decomposed with methanol and concentrated in vacuo, stirred into ice-water and taken up with methylene chloride, and the methylene chloride phase is washed, dried and concentrated. 130 mg of 17-(ethoxy-malonyloxy)-4-pregnene-3,20-dione melting at 119-121C. (from diisopropyl ether) are obtained.
UV:~239 = 18300-Example 39 , In a ~anner analogous to that in Example 38 1 gram of ~`
17-hydroxy-19-nor-4-pregnene-3,20-dione is reacted with malonic -~
acid mono-ethyl ester. After working up, 270 mg of 17-(ethoxy-malonyloxy)-l9-nor-4-pregene-3,20-dione melting at 121-122C.
(from ethanol) are obtained.
W: 239 = 17500.
Example 40 To a solution of 500 mg of 17-hydroxy-6a-methyl-4-pregnen-3,20-dione in 5 ml of dry methylene chloride is added -under nitrogen a freshly prepared solution of 436 mg of acetoxy-glycollic anhydride in dry ether. After the addition of 5 ~
litres of perchloric acid of 60% strength, the whole is allowed to stand for 24 hours, the reaction solution is decomposed with methanol and concentrated at room temperature in vacuo, in order to avoid splitting the undesired 3-enol-compound present in the mixture. The residue is chromatographed over silica gel.
17-(O-acetyl-glycoloyloxy)-6a-methyl-4-pregnen-3,20-dione is obtained.
Example 41 To 20 ml of benzene are added 530 mg of 3-acetoxy 'I
.,: , ~86~05 propionic acid, and 5 ml of the benzene are distilled off.
770 mg of trifluoracetic anh~dride are then added and the ;
whole is allowed to stand at room temperature for 1 hour.
While gassing with nitrogen 1 gram of 6-chloro-17-hydroxy-1~,2~-methylene-4,6-pregnadien-3,20-dione is added. The mixture is allowed to stand for 36 hours at room temperature, decomposed -~
with methanol, washed with sodium hydrogen carbonate solution -and concentrated _ vacuo. The residue is dissolved in 5 ml of methylene chloride and 5 ml of methanol, an ethanolic solution of potassium hydroxide is added and the mixture is allowed to stand under nitrogen for 3 hours at +5C. After acidification with acetic acid, ether is added and the mixture is washed neutral. After drying and concentrating, the residue is chromatographed over silica gel. 430 mg of 17-(3-acetoxy-propionoxy)-6-chloro-1~,2~-methylene-4,6-pregnadien-3-,20-dione ~, melting at 196-198C (from ethyl acetate) are obtained.
W : ~283 = 16900. `
Example 42 375 mg of thiodiglycollic acid are suspended in 20 ml of benzene and 500 mg of trifluoracetic anhydride are added.
After stirring for one hour, 400 mg of 4,6-dichloro-17-hydroxy-4,6-pregnadien-3,20-dione are added, and the whole is allowed to stand for 24 hours at room temperature. The mixture is then stirred into ice-water, adjusted to a pH-value of 8 with sodium hydroxide solution, and the mixture is extracted with ether. The aqueous phase is then acidified with 2N-sulphuric acid, the precipitated product is brought into solution with methanol and heated-for one hour under reflux. After cooling, the methanol is removed in vacuo and the precipitated product is filtered off with suction. It is washed with water until the thiodiglycollic acid is removed. It is dried ln vacuo, and 260 mg of 17-(carboxy-methylthioacetoxy)-4,6-dichloro-4,6-iO~3630S

pregnadien-3,20-dione are obtained.
Example 43 -500 mg of 17~-ethynyl-17~-hydroxy-4-oestren-3-one are dissolved in 5 ml of dry collidine, and, while cooling with ice and gassing with nitrogen,-800 mg of ~-acetoxy-isobutyryl `
chloride are added. The mixture is heated for 3 hours at 70C., cooled, a further 2 ml of collidine is added, and 180 mg of 4-dimethylamino-pyridine and a further 0.8 gram of acid chloride are added. After further heating at 70C. for 16 hours, the mixture is cooled, and worked up in a manner analogous to that -in Example 12. 270 mg of 17~-(O-acetyl-dimethylglycoloyloxy)-17~-ethynyl-4-oestren-3-one are obtained.
Example 44 50 mg of 17-carboxymethylthio-acetoxy)-4,6-dichloro- ; ~
4,6-pregnadien-3,20-dione are dissolved in 5 ml of ether/tetra- ~ ~?
hydrofurane mixture, and an etheral solution of diazomethane is added. The mixture is allowed to stand for one hour, then concentrated and chromatographed over silica gel. 51 mg of ~ ;
4,6-dichloro-17-(methoxycarbonylmethylthio-acetoxy)-4,6-pregnadien-3,20-dione are obtained.
Example 45 ;
500 mg of 6-chloro-17-hydroxy-1~,2~-methylene-4,6-pregnadien-3,20-dione are reacted with ethoxy-oxalyl chloride ;
in a manner analogous to that in Example 9. 420 mg of 17-(ethoxy-oxalyloxy)-6-chloro-1~,2~-methylene-4,6-pregnadien-3,20-dione melting at 193~C. (from diisopropyl ether) are obtained.
Example 46 An oily solution for intramuscular injection having a long lasting action.
, . _ ,- :
The injection solution is compounded by the usual methods under sterile conditions from the following constituents:

: ,, ~,- :,, :, : .
,~,. ... . ..

~0~6305 5000 mg of 17a-ethynyl-18-methyl-17~-(O-undecanoyl-glycoloyloxy)-4-oestren-3-one are dissolved in a mixture of castor oil/benzyl benzoate (6:4) and made up to 100 ml. The solution is charged in quantitites of 1 ml into ampoules, of which each contains 50 mg of active substance.
Example 47 A crystal suspension for intramuscular injection having a long lasting action.
.
The suspnesion is prepared by known methods and sterilised.
2000 mg of 17a-ethynyl-17~-(O-heptanoyl-glycoloyloxy)- ~ -18-methyl-4-oestren-3-one having a particle size smaller than 20 ~m are suspended in a physiological solution of sodium chloride, which contains 85 mg of Myrj 53(R), and made up to 100 ml. The suspension is charged in quantities of 1 ml into ampoules and sterilised. Each ampoule contains 20 mg of active ~;
substance.

, ;~,' ~

`

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the production of an ester of a phar-macologically active 17-hydroxy steroid having an unsubstituted alkynyl or chlorine-substituted alkynyl radical in the 17.alpha.-position or an unsubstituted acetyl or fluorine-substituted acetyl radical in the 17.beta.-position, with an acid of the general formula Z-COOH wherein Z represents X-OH, X-O-CO-Y-CO-OH, X-O-CO-R, X-O-CO-Y-CO-OR or X-O-SO2-R, in which X represents a saturated bivalent hydrocarbon radical having from 1 to 6 carbon atoms which may be uninterrupted or interrupted by one or more of the same or different atoms selected from oxygen and sulphur, and may be unsubstituted or substituted by one or more of the same or different substituents selected from -OH, -OCOR
and -OS02R groups, Y represents an alkylene group having 1 to 16 carbon atoms or 1,4-cyclohexylene or 1,4-phenylene group and R represents a hydrocarbon radical having from 1 to 22 carbon atoms which may be interrupted by at least one oxygen atom or a pharmaceutically acceptable salt thereof which comprises esterifying the hydroxy group of a pharmacologically active 17-hydroxy steroid with an acid of the formula Z-COOH or a reactive derivative thereof wherein Z is as above.

2. An ester of a pharmacologically active 17-hydroxy ;
steroid having an unsubstituted alkynyl or chlorine-substituted alkynyl radical in the 17.alpha.-position or an unsubstituted acetyl or fluorine-substituted acetyl radical in the 17.beta.-position, with an acid of the general formula Z-COOH wherein Z represents X-OH, X-O-CO-Y-CO-OH, X-O-CO-R, X-O-CO-Y-CO-OR or X-O-SO2-R,in which X represents a saturated bivalent hydrocarbon radical having from 1 to 6 carbon atoms which may be uninterrupted or interrupted by one or more of the same or different atoms selected from oxygen and sulphur, and may be unsubstituted or substituted by one or more of the same or different substituents from -OH, -OCOR and -OS02R groups, Y represents an alkylene group having from 1 to 16 carbon atoms, or a 1,4-cyclohexylene, or 1,4-phenylene group and R represents a hydrocarbon radical having from 1 to 22 carbon atoms which may be interrupted by at least one oxygen atom when prepared by the process as claimed in claim 1 or an obvious chemical equivalent thereof.

3. A process which comprises esterifying a steroid alcohol of the general formula ( IV) to an ester of the general formula - ( I ) in which each of the rings A, B, C and D may be unsubstituted or substituted, and may be saturated or unsaturated, R10 represents a hydrogen atom or a methyl group, R13 represents an alkyl group containing 1 to 3 carbon atoms, R17 represents an alkynyl group in the 17.alpha.-position or an acetyl group in the 17.beta.-position, Z represents a group of the general formula X-OH, X-O-CO-Y-CO-OH, X-O-CO-R, X-O-CO-Y-CO-OR or XOS02R, in which X represents a straight or branched alkylene group having from 1 to 6 carbon atoms which may be uninterrupted or interrupted by one or more oxygen or sulphur atoms, and the branched groups as well as the terminal groups may be substituted by -OH, -OCOR or -OS02R, Y represents an alkylene group which has 1 to 16 carbon atoms and which may be interrupted by one or more oxygen atoms, or a 1,4-phenylene or 1,4-cyclohexylene group and R represents a hydrocarbon radical containing 1 to 22 carbonatoms which may be interrupted by one or more oxygen atoms.

4. A process as claimed in claim 3, in which the hydroxy steroid of formula IV is first esterified with an acid of formula HO-X-CO-OH or COOH-Y-COOH

wherein X and Y are as in claim 3. and when required the product obtained further esterified with an acid of the formula R-COOH
HOOC-Y-COOH
or R-S020H

or an alcohol of formula R-OH

wherein R and Y are as in claim 3.

5. A depot-steroid ester of the general formula (I) in which each of the rings A, B, C and D may be unsubstituted or substituted, and may be saturated or unsaturated, R10 represents a hydrogen atom or a methyl group, R13 represents an alkyl group containing 1 to 3 carbon atoms, R17 represents an alkynyl group in the 17.alpha.-position or an acetyl group in the 17.beta.-position, Z

represents a group of the general formula X-OH, X-O-CO-Y-CO-OH, X-O-CO-R, X-O-CO-Y-CO-OR or X-O-S02-R, in which X represents a straight or branched alkylene group having from 1 to 6 carbon atoms which may be uninterrupted or interrupted by one or more oxygen atoms, and the branched groups as well as the terminal groups may be substituted by -OH, -OCOR or -OSO2R, Y
represents an alkylene group having 1 to 16 carbon atoms or a 1,4-phenylene or 1,4-cyclohexylene group and R represents a hydrocarbon radical containing 1 to 22 carbon atoms which may be interrupted by one or more oxygen atoms when prepared by the pro-cess as claimed in claim 3 or an obvious chemical equivalent thereof.

6. A process as claimed in claim 3, in which in the reactants the rings A, B, C and D are unsubstituted or substituted by one or more substituents selected from etherified and esteri-fied hydroxyl groups in the 1-, 2-, 3-, 4-, 7-, 11-, 15- and 16-positions, keto groups in the 3-, 6- and 11-positions, aliphatic groups having up to 5 carbon atoms in the 1-, 2-, 4-, 6-, 7- and 16-positions, methylene groups in the 1,2-, 6,7- and 15,16- posi-tions and halogen atoms in the 2-, 4-, 6-, 7-, 9-, 11- and 16-positions, and are saturated or contain a double bond on one or more positions selected from the 1(2)-, 3(4)-, 4(5)-, 5(10)-, 5(6)-, 6(7)-, 9(10)-, 9(11)-, 11(12)- and 15(16)- positions.

7. An ester as claimed in claim 2, wherein the rings A, B, C and D are unsubstituted or substituted by one or more substituents selected from etherified and esterified hydroxyl groups in the 1-, 2-, 3-, 4-, 7-, 11-, 15- and 16-positions, keto groups in the 3-, 6- and 11 positions, aliphatic groups having up to 5 carbon atoms in the 1-, 2-, 4-, 6-, 7- and 16- positions, methylene groups in the 1,2-, 6,7- and 15,16- positions and halo-gen atoms in the 2-, 4-, 6-, 7-, 9-, 11- and 16- positions, and are saturated or contain a double bond in one or more positions selected from the 1(2)-, 3(4)-, 4(5)-, 5(10)-, 5(6)-, 6(7)-, 9(10)-, 9(11)-, 11(12)- and 15(16)- positions when prepared by the process as claimed in claim 6 or an obvious chemical equiva-lent thereof.

8. A process as claimed in claim 6, in which in the reactants the 17a-substituent is ethynyl, chlorethynyl, propynyl or butadiynyl.

9. An ester as claimed in claim 2, wherein the 17.alpha.-substituent is ethynyl, chloroethynyl, propynyl or butadiynyl when prepared by the process as claimed in claim 8 or an obvious chemical equivalent thereof.

10. A process as claimed in claim 8, in which in the reactants 17.alpha.-substituent is ethynyl.

11. An ester as claimed in claim 5, wherein the 17.alpha.-substituent is ethynyl when prepared by the process as claimed in claim 10 or an obvious chemical equivalent thereof.,

12. A process as claimed in claim 3, in which the reactant steroid alcohol has the formula wherein R13 is as in claim 3,and the broken lines represents optional second carbon-to-carbon bonds, A represents the grouping or R10 represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom, a lower acyl, alkyl-sulphonyl, alkyl or cycloalkyl group, W = H2, O or H, OR3, ? represents a double bond in the 4,5-, 5,6- or 5,10-position and R15 and R16 each represents a hydrogen atom or both together represent a methylene group in the .alpha.- or .beta.-position or a further carbon-to-carbon bond between the carbon atoms C15 and C16.

13. Depot-steroid esters having the general formula II

(II) in which R13 and Z have the meanings given in claim 3, and the broken lines represent optional second carbon-to-carbon bonds, A
represents the grouping or R10 represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom, a lower acyl, alkylsulphonyl, alkyl or cycloalkyl group, W = H2, O or H, OR3, represents a double bond in the 4,5-, 5,6- or 5,10-? position and R15 and R16 each represent a hydrogen atom or both together represent a methylene group in the .alpha.- or .beta.-position or a further carbon-to-carbon bond between the carbon atoms C15 and C16 when prepared by the process as claimed in claim 12 or an obvious chemical equivalent thereof.

14. A process as claimed in claim 3, in which the reactant steroid has the formula in which R10, R13 and Z have the meanings given for formula I in claim 3 R1 and R2 each represent a hydrogen atom or both together repre-sent a methylene group or a further carbon-to-carbon bond between the carbon atoms C1 and C2, R4 represents a hydrogen or a chlorine atom, R6 represents a hydrogen, a chlorine atom or a methyl group, and --- represents a single or double bond between the carbon atoms C6 and C7.

15. Depot steroid esters characterized by the general formula III

in which R10, R13 and Z have the meanings given for formula I in claim 3, R1 and R2 each represent a hydrogen atom or both together represent a methylene group or a further carbon-to-carbon bond between the carbon atoms C1 and C2, R4 represents a hydrogen or a chlorine atom, R6 represents a hydrogen, a chlorine atom or a methyl group, and ---- represents a single or double bond between the carbon atoms C6 and C7 when prepared by the process as claimed in claim 14 or an obvious chemical equivalent thereof.

16. A process as claimed in claim 3, which comprises reacting the steroid alcohol of formula IV with crotonic acid in the presence of trifluoracetic anhydride to form the 17-crotonic acid esters, oxidizing the product obtained after protecting any keto groups present with potassium permanganate in the presence of formic acid at temperatures around the freezing point to form 2,3-dihydroxy-butyric acid esters, oxidatively splitting the product obtained with periodate to form the 17-glyoxalic acid esters, reducing the 17-glyoxalic acid esters so obtained with alkali metal boranate or lithium tri-tert.-butoxy alanate to form the 17-glycollic acid esters and liberating any protected keto groups.

17. Depots steroid esters of the formula Ia (Ia) in which the rings A, B, C and D may be substituted in any desired (usual) manner, R10 represents hydrogen or methyl, R13 represents alkyl containing 1-3 carbon atoms, and R17 represents alkinyl in the 17.alpha.-position or acetyl in the 17.beta.-position when prepared by the process as claimed in claim 16 or an obvious chemical equivalent thereof.

18. A process as claimed in claim 1 which comprises reacting crotonic acid with 17.alpha.-ethynyl-17.beta.-hydroxy-18-methyl-4-oestren-3-one in benzene and in the presence of trifluoro acetic anhydride.

19. 17.alpha.-Ethynyl-17.beta.-crotonoyloxy-18-methyl-4-oestren-3-one when prepared by the process as claimed in claim 18 or an obvious chemical equivalent thereof.

20. A process as claimed in claim 18, in which the product obtained is reacted with 2,2-dimethyl-1,3-propanediol in methylene chloride in the presence of para-toluene sulfonic acid and with formic acid triethylester, oxidizing the 17.alpha.-ethynyl-17.beta.-crotonoyloxy-3,3(2,2-dimethyl-trimethylenedioxxy)-18-methyl-5- and 5(10)-oestrene so obtained in acetone and water with potassium permanganate in acetone in an ice-bath, treating the 17.alpha.-ethinyl-17.beta.(2,3-dihydroxy-butyroxy)-3,3(2,2-diimethyl-tri-methylenedioxy)-18-methyl-5- and 5(10)-oestrene so obtained in dioxane and water with sodium periodate,treating the 17.alpha.-ethynyl-3,3(2,2-dimethyl-trimethylenedioxy)-17.beta.-glyoxoyloxxy-18-methyl-5-and 5(10)-oestrene so obtained in methanol with sodium boranate.

21. 17.alpha.-Ethynyl-3,3-(2,2-dimethyl-trimethylenedioxy)-17.beta.-glycoloyloxy-18-methyl-5- and 5(10)-oestrene when prepared by the process as claimed in claim 20 or an obvious chemical equiva-lent thereof.

22. A process as claimed in claim 20, in which the 17.alpha.-ethynyl-3,3(2,2-dimethyl-trimethylenedioxy)-17.beta.-gllycoloyloxy-18-methyl-5- and 5(10)-oestrene so obtained is treated with propionic anhydride in the presence of pyridine and the 17.alpha.-ethynyl-3,3(2,2-dimethyl-trimethylenedioxy)-18-methyl-17.beta.-(O-propiionyl-glycoloyloxy)-5- and 5(10)-oestrene so obtained is heated under reflux with oxalic acid in aqueous methanol.

23. 17 -Ethynyl-18-methyl-17.beta.-(O-propionyl-glycolyoyl-oxy)-oestren-3-one when prepared by the process as claimed in claim 22 or an obvious chemical equivalent thereof.

24. A process as claimed in claim 20 in which the 17.alpha.-ethynyl-3,3(2,2-dimethyl-trimethylenedioxy)-17.beta.-gllycoloyloxy-18-methyl-5- and 5(10)-oestrene so obtained is treated with oenanthic anhydride in the presence of pyridine and the 17a-ethynyl-3,3(2,2-dimethyl-trimethylenedioxy)-17.beta.-(O-heptanoylglycoloyloxy)18-methyl-5- and 5(10)-oestrene so obtained is heated under reflux with oxalic acid in aqueous methanol.

25. 17.alpha.-Ethynyl-17.beta.-(O-heptanoyl-glycoloyloxy)-18-methyl-4-oestren-3-one when prepared by the process as claimed in claim 24 or an obvious chemical equivalent thereof.

26. A process as claimed in claim 20 in which the 17.alpha.-ethynyl-3,3(2,2-dimethyl-trimethylenedioxy)-17.beta.-glycoloyloxy-18-methyl-5- and 5(10)-oestrene so obtained is treated with undecan-oic acid chloride in the presence of pyridine and the 17.alpha.-ethynyl-3,3(2,2-dimethyl-trimethylenedioxy)-18-methyl-17.beta.-(O-undecanoyl-glycoloyloxy)-5- and 5(10)-oestrene so obtained heated under reflux with oxalic acid in aqueous methanol.

27. 17.alpha.-Ethynyl-18-methyl-17.beta.-(O-undecanoyl-glycoloyl-oxy)-4-oestren-3-one when prepared by the process as claimed in claim 26 or an obvious chemical equivalent thereof.

28. A process as claimed in claim 20, in which the 17.alpha.-ethynyl-3,3(2,2-dimethyl-trimethylenedioxy)-18-methyl-17.beta.-glyco-loyloxy-5- and 5(10)-oestrene so obtained is treated with sulphuric acid in methanol.

29. 17.alpha.-Ethynyl-17.beta.-glycoloyloxy-18-methyl-4-oestren-3-one when prepared by the process as claimed in claim 28 or an obvious chemical equivalent thereof.

30. A process as claimed in claim 28, in which the 17.alpha.
ethynyl-17.beta.-glycoloyloxy-18-methyl-4-oestren-3-one so obtained is reacted with 3-cyclopentyl-propionyl chloride in the presence of pyridine.

31. 17d-Ethynyl-17.beta.-[O-(3-cylopentylpropionyl)-gly-coloyloxy]-18-methyl-4-oestren-3-one when prepared by the process as claimed in claim 30 or an obvious chemical equivalent thereof.

32. A process as claimed in claim 1, which comprises reacting 2-nonanoyloxy propionyl chloride with 17.alpha.-ethynyl-17.beta.-hydroxy-18-methyl-4-oestren-3-one in the presence of collidine and 4-dimethyl amino pyridine.

33. 17.alpha.-Ethynyl-17.beta.-(2-nonanoyloxy-propionoxy)-18-methyl-4-oestren-3-one when prepared by the process as claimed in claim 32 or an obvious chemical equivalent thereof.

34. A process as claimed in claim 1, which comprises reacting 3-acetoxy propionic acid in benzene and in the presence of trifluoroacetic anhydride with 17.alpha.-ethynyl-17.beta.-hydroxy-18-methyl-4-oestren-3-one.

35. 17.beta.-(3-Acetoxy-propionoxy)-17.alpha.-ethynyl-18-methyl-4-oestren-3-one when prepared by the process as claimed in claim 34 or an obvious chemical equivalent thereof.

36. A process as claimed in claim 34, in which the 17.beta.-(3-acetoxy-propionoxy)-17.alpha.-ethynyl-18-methyl-4-oestren-3-one is treated in methanolic methylene chloride with an ethanolic solu-tion of potassium hydroxide.

37. 17.alpha.-Ethynyl-17.beta.-(3-hydroxy-propionoxy)-18-methyl-4-oestren-3-one when prepared by the process as claimed in claim 36 or an obvious chemical equivalent thereof.

38. A process as cIaimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-hydroxy-4-oestren-3-one in the presence of collidine and 4-dimethyl amino pyridine with acetoxy glycolyl chloride.

39. 17.beta.-(0-Acetyl-glycoloyloxy)-17.alpha.-ethynyl-4-oestren-3-one when prepared by the process as claimed in claim 38 or an obvious chemical equivalent thereof.

40. A process as claimed in claim 38, in which the 17.beta.-(O-acetyl-glycoloyloxy)-17.alpha.-ethynyl-4-oestren-3-one so obtained is treated with an ethanolic solution of potassium hydroxide in methylene chloride/methanol.

41. 17.alpha.-Ethynyl-17.beta.-glycoloyloxy-4-oestren-3-one when prepared by the process as claimed in claim 40 or an obvious chemi-cal equivalent thereof.

42. A process as claimed in claim 40, in which the 17.alpha.-ethynyl-17.beta.-glycoloyloxy-4-oestren-3-one so obtained is reacted with 3,6,9-trioxa-isododecanoyl chloride in dry pyridine.

43. 17.alpha.-Ethynyl-17.beta.-(0-10-methyl-3,6,9-trioxaundecanoyl-glycoloyloxy)-4-oestren-3-one when prepared by the process as claimed in claim 42 or an obvious chemical equivalent thereof.

44. A process as claimed in claim 40, in which the 17 ethynyl-17.beta.-glycoloyloxy-4-oestren-3-one so obtained is reacted with 0-4-octyloxy-benzoyl chloride in pyridine.

45. 17.alpha.-Ethynyl-17.beta.-[0-(4-octyloxy-benzoyl)-glycoloyl-oxy]-4-oestren-3-one when prepared by the process as claimed in claim 44 or an obvious chemical equivaient thereof.

46. A process as claimed in claim 40, in which the 17.alpha.-ethynyl-17.beta.-glycoloyloxy-4-oestren-3-one so obtained is reacted with 0-4-octyloxycarbonyl-cyclohexyl carbonylchloride in pyridine.

47. 17.alpha.-Ethynyl-17.beta.-[0-(4-octyloxycarbonyl-cyclohexyl-carbonyl)-glycoloyloxy]-4-oestren-3-one when prepared by the pro-cess as claimed in claim 46 or an obvious chemical equivalent thereof.

48. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-hydroxy-4-oestren-3-one in the presence of collidine and 4-dimethylaminopyridine with 4-undecanoyloxy-cyclohexane-carbonyl chloride.

49. 17.alpha.-Ethynyl-17.beta.- (4-undecanoyloxy-cyclohexyl-carbonyloxy)-4-oestren-3-one when prepared by the process as claimed in claim 48 or an obvious chemical equivalent thereof.

50. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-hydroxy-4-oestrene with acetoxy glycolyl chloride in the presence of collidine and dimethyl amino pyridine

51. 17.beta.-(0-Acetyl-glycoloyloxy)-17.alpha.-ethynyl-4-oestrene when prepared by the process as claimed in claim 50 or an obvious chemical equivalent thereof.

52. A process as claimed in claim 50, in which the 17 (O-acetyl-glycoloyloxy)-17.alpha.-ethynyl-4-oestrene so obtained is treated with ethanolic potassium hydroxide in methanol and methylene chloride.

53. 17.alpha.-Ethynyl-17.beta.-glycoloyloxy-4-oestrene when pre-pared by the process as claimed in claim 52 or an obvious chemical equivalent thereof.

54. A process as claimed in claim 52 in which the 17.alpha.-ethynyl-17.beta.-glycoloyloxy-4-oestrene so obtained is reacted with stearoyl chloride in the presence of dry pyridine.

55. 17.alpha.-Ethynyl-17.beta.-(O-stearoyl-glycoloyloxy)-4-oestrene when prepared by the process as claimed in claim 54 or an obvious chemical equivalent thereof.

56. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-hydroxy-5(10)-oestren-3-one in the presence of collidine and dimethylamino pyridine with O-undecanoyl-glycoloyl chloride.

57. 17.alpha.-Ethynyl-17.beta.-(O-undecanoyl-glycoloyloxy-5(10)-oestren-3-one when prepared by the process as claimed in claim 56 or an obvious chemical equivalent thereof.

58. 17.alpha.-Ethynyl-17.beta.-(O-undecanoyloxy-glycoloyloxy)-4-oestren-3-one when prepared by the process as claimed in claim 56 or an obvious chemical equivalent thereof.

59. A process as claimed in claim 1, which comprises reacting 17a-ethynyl-3-methoxy-1,3,5(10)-oestratrien-17.beta.-ol in the presence of collidine and dimethyl amino pyridine with acetoxy glycoloyl chloride.

60. 17.beta.-(O-Acetyl-glycoloyloxy)-17.alpha.-ethynyl-3-methoxy-1,3,5(10)-oestratriene when prepared by the process as claimed in claim 59 or an obvious chemical equivalent thereof.

61. A process as claimed in claim 59, in which the 17.beta.-(O-acetyl-glycoloyloxy)-17.alpha.-ethynyl-3-methoxy-1,3,5(10)-oestratriene so obtained is treated with ethanolic potassium hydroxide in methanol/methylene chloride.

62. 17.alpha.-Ethynyl-17.beta.-glycoloyloxy-3-methoxy-1,3,5(10)-oestratriene when prepared by the process as claimed in claim 61 or an obvious chemical equivalent thereof.

63. A process as claimed in claim 61 in which the 17.alpha.-ethynyl-l7.beta.-glycoloyloxy-3-methoxy-l,3,5(10)-oestratriene so obtained is treated with isovaleryl chloride in dry pyridine.

64. 17.alpha.-Ethynyl-17.beta.-(O-isovaleryl-glycoloyloxy)-3-methoxy-1,3,5(10)-oestratriene when prepared by the process as claimed in claim 63 or an obvious chemical equivalent thereof.

65. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-hydroxy-1,3,5(10)-oestratrien-3-ol in the presence of collidine and dimethyl amino pyridine with O-undecanoyl-glycoloyl chloride.

66. 17.alpha.-Ethynyl-17.beta.-(O-undecanoyl-glycoloyloxy)-1,3,5-(10)-oestratrien-3-ol when prepared by the process as claimed in claim 65 or an obvious chemical equivalent thereof.

67. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-3-cyclopentyloxy-17.beta.-hydroxy-1,3,5(10)-oestratriene in the presence of collidine and dimethyl amino pyridine with O-undecanoyl-glycoloyl chloride.

68. 17.alpha.-Ethynyl-3-cyclopentyloxy-17.beta.-(O-undecanoyl-glycoloyloxy)-1,3,5(10)-oestratriene when prepared by the process as claimed in claim 67 or an obvious chemical equivalent thereof.

69. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-hydroxy-3-(propan-2-sulphonyloxy)-1,3, 5(10)-oestratriene in the presence of collidine and dimethyl amino pyridine with O-valeryl-glycoloyl chloride.

70. 17.alpha.-Ethynyl-3-(isopropyl-sulphonyloxy)-17.beta.-(O-valeryl-glycoloyloxy)-1,3,5(10)-oestratriene when prepared by the process as claimed in claim 69 or an obvious chemical equivalent thereof.

71. A process as claimed in claim 40, in which the 17.alpha.-ethynyl-17.alpha.-glycoloyloxy-4-oestren-3-one so obtained is reacted in isopropyl sulphonyl chloride in benzene and in the presence of triethylamine.

72. 17.alpha.-Ethynyl-17.beta.-(O-isopropyl-sulphonyl-glycoloyl-oxy)-4-oestren-3-one when prepared by the process as claimed in claim 71 or an obvious chemical equivalent thereof.

73. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-hydroxy-4-androsten-3-one with O-undecan-oyl glycoloyl chloride in the presence of collidine.

74. 17.alpha.-Ethynyl-17.beta.-(O-undecanoyl-glycoloyloxy)-4-androsten-3-one when prepared by the process as claimed in claim 73 or an obvious chemical equivalent thereof.

75. A process as claimed in claim 1, which comprises reacting 3.beta.-aceioxy-lla-ethynyl-17.beta.-hydroxy-4-oestrene with O-unaecanoyl-glycoloyl chloride in the presence of collidine.

76. 3.beta.-Acetoxy-17.alpha.-ethynyl-17.beta.-(0-undecanoyl-glycoloyl-oxy)-4-oestrene when prepared by the process as claimed in claim 75 or an obvious chemical equivalent thereof.

77. A process as claimed in claim 38, in which the 17.beta.-(0-acetyl-glycoloyloxy)-17.alpha.-ethynyl-4-oestren--3-one so obtained is reacted in dioxane and in the presence of paratoluene sulphonic acid with ortho formic acid ethyl ester and pyridine is added thereto and the 3-ethoxy-3,5-diene so obtained is reacted in benzene and in the presence of paratoluene sulphonic acid with cyclopentanol.

78. 17.beta.-(O-Acetyl-glycoloyloxy)-17.alpha.-ethynyl-3-cyclo-pentyloxy-3,5-oestradiene when prepared by the process as claimed in claim 77 or an obvious chemical equivalent thereof.

79. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-hydroxy-18-ethyl-4-oestren-3-one with 3-menthoxy-undecandioyloxy propionic acid in benzene and in the presence of trifluoroacetic anhydride.

80. 17.alpha.-Ethynyl-18-ethyl-17.beta.-[3-(methoxy-undecandioyl-oxy)-propionoxy]-4-oestren-3-one when prepared by the process as claimed in claim 79 or an obvious chemical equivalent thereof.

81. A process as claimed in claim 1, which comprises reacting crotonic acid with 17.alpha.-ethynyl-17.beta.-hydroxy-18-methyl-15.alpha.,16.alpha.-methylene-4-oestren-3-one in benzene and in the presence of trifluoro acetic anhydride, reacting the product obtained with 2,2-dimethyl-1,3-propane diol in methylene chloride and in the presence of para-toluene sulphonic acid and orthoformic acid triethyl ester, oxidizing the product obtained in acetone and in the presence of formic acid with potassium permanganate in aqueous acetone, treating the product obtained with sodium periodate in aqueous dioxane, treating the product obtained with sodium boranate in aqueous methanol, reacting the product obtained with propionic anhydride in the presence of pyridine and reflux-ing the product obtained in aqueous methanol with oxalic acid.

82. 17.beta.-(O-propionyl-glycoloyloxy)-17.alpha.-ethynyl-18-methyl-15.alpha.,16.alpha.-methylene-4-oestren-3-one when prepared by the process as claimed in claim 81 or an obvious chemical equivalent thereof.

83. A process as claimed in claim 1, which comprises reacting crotonic acid with 17.alpha.-ethynyl-17.beta.-hydroxy-18-methyl-15.alpha.,16.beta.-methylene-4-oestren-3-one in benzene and in the presence of trifluoro acetic anhydride, reacting the product obtained with 2,2-dimethyl-1,3-propane diol in methylene chloride and in the presence of para-toluene sulphonic acid and orthoformic acid triethyl ester, oxidizing the product obtained in acetone and in the presence of formic acid with potassium permanganate in aqueous acetone, treating the product obtained witn sodium periodate in aqueous dioxane, treating the product obtained with sodium boranate in aqueous methanol, reacting the product obtained with propionic anhydride in the presence of pyridine and reflux-ing the product obtained in aqueous methanol with oxalic acid.

84. 17.beta.-(O-propionyl-glycoloyloxy)-17.alpha.-ethynyl-18-methyl-15.beta.,16.beta.-methylene-4-oestren-3-one when prepared by the process as claimed in claim 83 or an obvious chemical equivalent thereof.

85. A process as claimed in claim 1, which comprises reacting 4-acetoxy butyric acid in benzene with 4,6-dichloro-17-hydroxy-l.alpha.,2.alpha.-methylene-4,6-pregnadien-3,20-dione in the presence of trifluoro acetic anhydride.

86. 17-(4-acetoxy-butyroxy)-4,6-dichloro-1.alpha.,2.alpha.-methyl-ene-4,6-pregnadien-3,20-dione when prepared by the process as claimed in claim 85 or an obvious chemical equivalent thereof.

87. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-hydroxy-4,9(10),11(123-oestratrien-3-one in the presence of trifluoroacetic anhydride with 3-acetoxy-propionic acid.

88. 17.beta.-(3-Acetoxy-propionoxy)-17.alpha.-ethynyl-4,9(10), 11(12),oestratrien-3-one when prepared by the process as claimed in claim 87 or an obvious chemical equivalent thereof.

89. A process as claimed in claim 1, which comprises reacting under nitrogen 17-hydroxy-6.alpha.-methyl-4-prPgnen-3,20-dione in dry methylene chloride in dry ether with acetoxy glycollic anhydride and in the presence of perchloric acid.

90. 17-(O-Acetyl-glycoloyloxy)-6.alpha.-methyl-4-pregnen-3,20-dione when prepared by the process as claimed in claim 89 or an obvious chemical equivalent thereof.

91. A process as claimed in claim 1, which comprises reacting 3-acetoxy propionic acid in benzene and in the presence of trifluoro acetic anhydride with 6-chloro-17-hydroxy-1.alpha.,2.alpha.-methylene-4,6-pregnadien-3,20-dione and treating the product obtained with ethanolic potassium hydroxide in methylene chloride.

92. 17-(3-Acetoxy-propionyloxy)-6-chloro-1.alpha.,2.alpha.-methyl-ene-4,6-pregnadien-3,20-dione when prepared by the process as claimed in claim 91 or an obvious chemical equivalent thereof.

93. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-hydroxy-4-oestren-3-one with .alpha.-acetoxy isobutryl chloride in the presence of collidine and 4-dimethyl amino pyridine.

94. 17.beta.-(O-Acetyl-dimethylglycoloyloxy)-17.alpha.-ethynyl-4-oestren-3-one when prepared by the process as claimed in claim 93 or an obvious chemical equivalent thereof.

95. A process as claimed in claim 28, in which tri-decanoyl chloride is reacted with the 17.alpha.-ethynyl-17.beta.-glycoloy-loxy-18-methyl-4-oestren-3-one so obtained.

96. 17.alpha.-Ethynyl-17.beta.-(O-tridecanoyl-glycoloyloxy)-18-methyl-4-oestren-3-one when prepared by the process as claimed in claim 95 or an obvious chemical equivalent thereof.

97. A process as claimed in claim 40, in which the 17.alpha.-ethynyl-17.beta.-glycoloyloxy-4-oestren-3-one so obtained is reacted with tridecanoyl chloride in the presence of pyridine.

98. 17.alpha.-Ethynyl-17.beta.-(O-tridecanoyl-glycoloyloxy)-4-oestren-3-one when prepared by the process as claimed in claim 97 or an obvious chemical equivalent thereof.

99. A process as claimed in claim 40, in which the 17.alpha.-ethynyl-17.beta.-glycoloyloxy-4-oestren-3-one so obtained is reacted with hexadecanoyl chloride in the presence of pyridine.

100. 17.alpha.-Ethynyl-17.beta.-(O-hexadecanoyl-glycoloyloxy)-4-oestren-3-one when prepared by the process as claimed in claim 99 or an obvious chemical equivalent thereof.

101. A process as claimed in claim 40, in which the 17.alpha.-ethynyl-17.beta.-glycoloyloxy-4-oestren-3-one so obtained is reacted with octadecanoyl chloride in the presence of pyridine.

102. 17.alpha.-Ethynyl-17.beta.-(O-octadecanoyl-glycoloyloxy)-4-oestren-3-one when prepared by the process as claimed in claim 101 or an obvious chemical equivalent thereof.

103. A process as claimed in claim 1, which comprises reacting 17.alpha.-ethynyl-17.beta.-glycoloyloxy-18-methyl-4,15-oestradien-3-one with tridecanoyl chloride in the presence of pyridine.

104. 17.alpha.-Ethynyl-17.beta.-(O-tridecanoyl-glycoloyloxy)-18-methyl-4,15-oestradien-3-onewhen prepared by the process as claimed in claim 103 or an obvious chemical equivalent thereof.